TUBA4A was first reported in relation to autosomal dominant macrothrombocytopenia in 2019 (Strassel et al., 2019, PMID: 30760556). TUBA4A encodes an α-tubulin subunit, which together with β-tubulin constitutes the tubulin heterodimer, the building block of microtubules and it is well established that microtubules are key actors in the formation of proplatelets from mature megakaryocytes (Reviewed in PMID: 31315202). Evidence supporting this gene-disease relationship includes case-level data and experimental data. One macrothrombocytopenia patient has been reported with two rare TUBA4A missense variants in cis (PMID: 30760556). No functional evidence is yet available to support one, or both, variants as deleterious. This gene-disease relationship is supported by its shared function with TUBB1 as a building block of microtubules. TUBA4A has a high level of microtubule incorporation (PMID: 25374358) and expression of TUBA4A is particularly enriched in platelet microtubules (PMID: 30760556). Additionally, mice carrying a missense mutation in the Tuba4a gene, displayed macrothrombocytopenia and structural abnormalities in the marginal band of platelets, similar to the patient. In summary, there is limited evidence to support this gene-disease relationship. There is very limited genetic evidence based and more evidence is needed to support a causal role, however no convincing evidence has emerged that contradicts the gene-disease relationship.
Of note, TUBA4A has also been implicated in autosomal dominant amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. and apparently dominant negative TUBA4A variants are suggested to dysregulate neuronal function by disruption of microtubule dynamics and stability. Based on differences in phenotype and proposed molecular mechanisms these disease entiteis have been considered seperately and the relationship to ALS was curated by the ALS GCEP.
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